Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella

Science. 2020 Jul 24;369(6502):450-455. doi: 10.1126/science.aaz1333.


The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as Salmonella Here, we show that this mechanism requires aconitate decarboxylase 1 (IRG1), which synthesizes itaconate, a metabolite with antimicrobial activity. We find that Rab32 interacts with IRG1 on Salmonella infection and facilitates the delivery of itaconate to the Salmonella-containing vacuole. Mice defective in IRG1 rescued the virulence defect of a S. enterica serovar Typhimurium mutant specifically defective in its ability to counter the Rab32 defense mechanism. These studies provide a link between a metabolite produced in the mitochondria after stimulation of innate immune receptors and a cell-autonomous defense mechanism that restricts the replication of an intracellular bacterial pathogen.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Line
  • Host-Pathogen Interactions
  • Humans
  • Hydro-Lyases / immunology*
  • Hydro-Lyases / metabolism
  • Mice
  • Salmonella Infections / immunology*
  • Salmonella Infections / metabolism
  • Salmonella Infections / microbiology
  • Salmonella enterica*
  • Salmonella typhimurium*
  • Succinates
  • Virulence
  • rab GTP-Binding Proteins / immunology*
  • rab GTP-Binding Proteins / metabolism


  • Succinates
  • Rab32 protein, mouse
  • rab GTP-Binding Proteins
  • Hydro-Lyases
  • Irg1 protein, mouse
  • itaconic acid